Faculty Bibliography

Focal therapy of prostate cancer is an evolving treatment strategy that destroys a predefined region of the prostate gland that harbors clinically significant disease. Although long-term oncologic control has yet to be demonstrated, focal therapy is associated with a marked decrease in treatment-related morbidity. Focal laser ablation is an emerging modality that has several advantages, most notably real-time magnetic resonance imaging (MRI) compatibility. This review presents the principles of laser ablation, the role of multiparametric MRI for delineating the site of significant prostate cancer, a summary of published clinical studies, and our initial experience with 23 patients, criteria for selecting candidates for focal prostate ablation, and speculation regarding future directions.

Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the AR at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild-type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine-to-alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand-independent manner and cell type-specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression, AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR-mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild-type AR, but not S213A mutant AR. Androgen-mediated transcription of endogenous PSA, Nkx3.1 and IGFBP5 was also decreased in the presence of PIM1, whereas IL6, cyclin A1 and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.Oncogene advance online publication, 17 September 2012; doi:10.1038/onc.2012.412.

IMPORTANCE: Soy consumption has been suggested to reduce risk or recurrence of prostate cancer, but this has not been tested in a randomized trial with prostate cancer as the end point. OBJECTIVE: To determine whether daily consumption of a soy protein isolate supplement for 2 years reduces the rate of biochemical recurrence of prostate cancer after radical prostatectomy or delays such recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial conducted from July 1997 to May 2010 at 7 US centers comparing daily consumption of a soy protein supplement vs placebo in 177 men at high risk of recurrence after radical prostatectomy for prostate cancer. Supplement intervention was started within 4 months after surgery and continued for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter. INTERVENTION: Participants were randomized to receive a daily serving of a beverage powder containing 20 g of protein in the form of either soy protein isolate (n=87) or, as placebo, calcium caseinate (n=90). MAIN OUTCOMES AND MEASURES: Biochemical recurrence rate of prostate cancer (defined as development of a PSA level of >/=0.07 ng/mL) over the first 2 years following randomization and time to recurrence. RESULTS: The trial was stopped early for lack of treatment effects at a planned interim analysis with 81 evaluable participants in the intervention group and 78 in the placebo group. Overall, 28.3% of participants developed biochemical recurrence within 2 years of entering the trial (close to the a priori predicted recurrence rate of 30%). Among these, 22 (27.2%) occurred in the intervention group and 23 (29.5%) in the placebo group. The resulting hazard ratio for active treatment was 0.96 (95% CI, 0.53-1.72; log-rank P = .89). Adherence was greater than 90% and there were no apparent adverse events related to supplementation. CONCLUSION AND RELEVANCE: Daily consumption of a beverage powder supplement containing soy protein isolate for 2 years following radical prostatectomy did not reduce biochemical recurrence of prostate cancer in men at high risk of PSA failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00765479.

OBJECTIVE: To elucidate the probability that Gleason 6 tumors diagnosed in the prostate-specific antigen (PSA) era treated with radical prostatectomy (RP) develop metastasis. METHODS: Between October 2000 and June 2012, 1781 men underwent open RP by a single surgeon. Biochemical recurrence (BCR) was defined as a serum PSA value >/=0.2 ng/mL, or 2 progressively rising PSA values >0.14 ng/mL. Significant BCR (sBCR) was defined as a BCR with a PSA doubling time (PSADT) <36 months. Insignificant BCR (iBCR) was defined as BCR with a PSADT >/=36 months. RESULTS: Eight hundred fifty-seven of men (48.1%) undergoing open RP had a pathologic diagnosis of Gleason 6. Twenty-three of 857 of these men (2.7%) developed BCR, 7 were designated as iBCR (mean PSADT 81 months, range 36 to 100), 16 were sBCR (mean PSADT 8 months, range 1.5-20 months). There was a 10-fold difference in PSADT between the sBCR and iBCR groups (P <.001). All men with sBCR underwent salvage radiation therapy (SRT) and all demonstrated a subsequent PSA decline to